Discussion
To our knowledge, our study is the largest, multicenter, prospective study of CRRT conducted in critically ill children with SHLH-associated MODS. Furthermore, we additionally reported the first data on detailing the PICU course and outcome of these patients. We observed that patients with SHLH and MODS received CRRT in PICU was associated with a high PICU mortality at 46.2% (22/52). Our data also demonstrated that the number of organ dysfunction and serum IL-6 level at CRRT initiation higher than 3 and 13.12pg/ml are independent risk factors of initial PICU mortality.
The overall mortality rate from HLH ranges across studies from 22 to 59%[12]. In recent years, a trend to a reduction in mortality among critically ill patients with SHLH admitted to the ICU was observed. In the sub-group of pediatric patients, the same trend was also found. In 2018, Gregory and colleagues described a single center experience of HLH in a PICU over a 10-year period, which including 42 patients, overall initial PICU hospitalization mortality and 1-year mortality was 21% and 42% respectively[13]. This outcome benefits may be owed to improvement in chemotherapy, multiple organ support technology and better intensive care management. Nevertheless, there is no published literature reporting mortality in SHLH-associated MODS patients required CRRT. In our registry, total initial PICU hospitalization mortality for our patient cohort was 46.2% (22/52). This may shed light onto the quite poor outcomes among patients with SHLH and MODS who need CRRT. Thus, the development of therapies targeted at preventing or limiting the progress of MODS is urgently needed.
MODS is the leading cause of hospital death in SHLH patients and the prognosis depends mainly on the number and severity of organ dysfunctions. Numerous studies reported over half of deaths occur within 30 days after SHLH diagnosis due to MODS or second infection[14,15]. Leow et al[16], assessed poor prognostic factors and mortality for pediatric patients with HLH admitted to the cardiac ICU, they found patients with a higher mortality index score at admission, higher serum lactate levels, the need for mechanical ventilation, vasoactives and CRRT were associated with higher mortality. Indeed, we demonstrated a correlation between the number of organ dysfunctions and mortality. Significantly, nonsurvivors had more respiratory, cardiovascular and gastrointestinal dysfunctions. Likewise, the use of organ support (mechanical ventilation, vasoactive agents) was also higher in the nonsurvivors.
Abrupt onset of rapid progress to MODS is common in fatal HLH patients[17] MODS is often reported at the advanced stage of SHLH and is related to abnormally higher concentrations of hypercytokinemia including interferon-γ(IFN-γ), tumoral necrosis factor-α (TNF-α), interleukin-10 (IL- 10), IL-6 and so on[18]. IL-6 amplifies TLR-induced inflammatory response also in cells originating from inflammatory site. In vitro, Claudia et al. demonstrated that, prolonged exposure of human macrophages to IL-6 leads to increased production of cytokines, including (C-X-C Motif) Ligand 8 (CXCL-8) and Tumor Necrosis Factor-α (TNF-α)[19]. A single-center study reported, renal failure was related to abnormally high concentrations of nephrotoxic interleukin-6 (IL-6) in serum[20]. Our data demonstrated that serum IL-6 levels was positively associated with the number of dysfunction organs on correlational analysis which corroborated similar findings from previous studies.
The prognostic significance of cytokines for early death has once been reported[21]. Tang et al[22] found high IFN-γ and IL-10 levels were associated with early death. It is worth noting that, in our study serum IL-6 levels at PICU admission was higher in the non-survivor group than survivor group. We further found that highly elevated IL-6 level (>13.12pg/mL) was an independent risk factor of hospital death in critically SHLH-associated MODS pediatric patients. This result was consistent with previous study of HLH, which showed patients in the non-survivors group had higher IL-6, IFN-γ and IL-10 levels[23]. IL-6 levels are usually significantly elevated in patients with sepsis, which is considered to be the major cause of mobility and mortality in pediatric SHLH patients[24]. This may partially explain the phenomenon of higher level of IL-6 in SHLH patients with death. As a result, it may be reasonable to consider IL-6 levels greater than13.12 pg/ml as a prognostic factor maker of SHLH.
Current management of SHLH-associated MODS includes prompt clinical stabilization with ICU-level organ supportive care, applying specific measures to control the hyperinflammation, identification and treatment of the underlying cause of SHLH and infectious complications. From the onset, aggressive interventions for the treatment of multiorgan dysfunction are usually conducted to stabilize the patient’s status while allowing time for other therapeutic strategy to treat SHLH. Management of the hyperinflammatory response focuses on blocking excessive cytokine production and eliminating the triggers are also important[14,25]. Medications, such as corticosteroids and immunosuppressants, are recommended in SHLH treatment to suppress the inflammatory response and control cell proliferation[9,26]. However, corticosteroids and immunosuppression leave many SHLH patients susceptible to infection, as well as secondary infections can trigger reactivation of the underlying hyperinflammatory response leading to additional morbidity and mortality.
CRRT as a new type of renal replacement, is being used more often in critically ill children with MODS. CRRT has been also recommended as an effective therapeutic for the treatment of systemic inflammatory syndromes. With regard to severe sepsis adjunctive therapies, inflammatory mediator modulation can be achieved through hemofiltration (HF) based CRRT mode, such as continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF). One of the mechanisms for the beneficial effect of HF in sepsis may be the convective clearance of soluble inflammatory mediators. Over the last few years, animal experiments and human studies have shown that, CVVH/CVVHDF can remove soluble inflammatory mediators of sepsis, as well as attenuate the severity of the response to sepsis. DiCarlo et al[27] demonstrated the utility of continuous hemofiltration in attenuating the consequences of excess cytokine activity and the degree of lactate in three HLH patients with MODS. Our previous single-center nonrandomized concurrent control trial showed high-volume hemofiltration (HVHF) may be an effective adjunctive treatment in SHLH/MAS by improving organ function and decreasing serum level of TNF-α and IL-6[8]. There are several small reports of treatment of SHLH with alternative therapeutics directed against IL-1, IL-6 and TNF-α in serum, which have demonstrated clinical benefits for these patients[28].
Our study has some limitations. First, gene sequencing was not performed in all patients, so that the proportion of FHL remained uncertain. Second, although this study was based on a multi-centered prospective study, relatively small number of patients was warranted to validate the results.